Progress to date: This study has now enrolled 124 subjects from the Children's Hospital of Philadelphia (CHOP), with samples recieved on 54. Ongoing attempts are underway to locate 3 controls for each case, and to locate cases lost to follow-up. Consent forms have been signed. Complete family histories have been obtained from these patients. Collection of blood and tumor samples for genotype testing is currently underway. In addition, for the GST analyses, DNA can be obtained from buccal smears and these are currently being collected in addition to blood specimens. We are continuing to receive updated information from the tumor registry regarding new cases that meet eligibility requirements. Preliminary Results: Between 1970 and 1996, 4796 children were treated for a primary malignancy at CHOP. Of these, 104 developed second malignant neoplasm (SMN), with an incidence density of 380 per 100,000 person-years. The estimated cumulative incidence is 2.3%. Further data analysis is underway to calculate SIR's for the most common second malignancies. Associations were found between certain specific primary and secondary malignancies. Primary Leukemia was associated with thyroid cancer (OR=4.9) or CNS tumor (OR=1.8). Patients with retinoblastoma or Ewing's sarcoma were more likely to develop osteosarcoma (OR=10.3 and 5.1 respectively). Epipodophyllotoxin exposure was associated with leukemia (OR=3.2). Radiation was associated marginally with a risk of secondary sarcoma (OR=1.3), and was synergistic with chemotherapy ((OR=2.1). CNS, thyroid and breast cancer (n=21) were seen only in patients who received radiation. Using case-control methodology, the role of family histories has been evaluted to date on 35 cases and 1-3 controls per case. There were no significant differences noted in gender or race between those with and without an SMN. Family history of congenital anomalies or hereditary syndromes was associated with a statistically non-significant increased risk of SMN (OR=2.5 and 4.0 respectively), as was family history of cancer in either first degree or second degree relatives (OR's 1.5 and 5.0 respectively). Several interesting family pedigrees have emerged among the cases. These will be explored further.